2. we performed a meta-analysis of randomized clinical trials aiming at
determining whether pre-procedural, short-term, intensive statin
administration is superior to conventional-dose statin, no statin, or
placebo for CI-AKI prevention in both ACS patients undergoing urgent
or emergency CA/PCI and in those without ACS electively referred to
CA and, if suitable, to PCI.
2. Methods
2.1. Search strategy
The study was designed according to the PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) state-
ment [19]. PubMED, MEDLINE, ISI Web of Science, and EMBASE data-
bases were searched for articles published between January 1st, 2003
and February 28th, 2014 combining the following search terms: “statins
AND (contrast OR radiocontrast OR contrast media) AND (contrast-in-
duced nephropathy OR nephropathy OR AKI OR acute renal failure)”.
Our decision to include all studies published since January 1st, 2003
was based on the consideration that the first evidence showing a bene-
ficial effect of statin pre-treatment on CI-AKI occurrence in patients un-
dergoing CA was reported in 2004 [20].
2.2. Study selection
Study inclusion criteria were: 1) age at randomization N18 years;
2) randomized allocation to treatment groups; 3) prospective studies
of individuals randomized to statins vs. a control group (who received
either lower statin dose, or no statin, or placebo before contrast admin-
istration); 4) pre-procedural administration, described as immediately
prior to or at least within 24 h before the planned contrast exposure;
5) English language literature only restriction; 6) trials reporting the in-
cidence of CI-AKI as the end point at 48 h or later after contrast admin-
istration. Data published in the form of abstracts without peer-reviewed
publication of the manuscripts or accepted as short communications or
brief reports were excluded.
2.3. Data extraction and quality assessment
Papers identified in the literature search were screened by 2
independent reviewers (NC and JPW) to assess their eligibility for the
analysis. Discrepancies were resolved by two senior authors (GM and
AB). From each study, information about year of publication, methods
and entry criteria, number of patients in treatment and control arms,
age, sex, clinical presentation (ACS vs. non-ACS patients), diabetes
mellitus rate, baseline renal function, statin type and dose, contrast
medium type and volume, and CI-AKI definition and incidence were ex-
tracted, tabularized and analyzed with SAS version 9.2, SAS Institute,
North Carolina, USA. The pre-specified outcome assessed from selected
trials was the difference in the incidence of CI-AKI between the two
groups, defined as an absolute increase in serum creatinine (sCr) con-
centration N0.5 mg/dL or as a relative increase N25%. Notably, when
included studies reported CI-AKI incidence both in terms of absolute
and relative increase in sCr, the outcome based on the relative change
was chosen for analysis due to the advantages of this approach [21].
Furthermore, when CI-AKI incidence was reported both at 48 h and
other time periods, the 48-hour incidence was considered for analysis,
since this is the most common time point used for CI-AKI definition. A
pre-specified subgroup analysis according to the clinical presentation
(ACS vs. non-ACS) was performed including eight studies: four enroll-
ing ACS patients only [15–18] and four enrolling non-ACS patients
only [5,9,10,12]. The study by Han et al. [4], included in the pooled anal-
ysis, was not considered in the subgroup analysis because a mixed
population of ACS and non-ACS patients participated in this study and
no information about the CI-AKI incidence according to the clinical pre-
sentation was available.
2.4. Statistical analysis
2.4.1. Data synthesis and analysis
Categorical variables were summarized as frequencies and quantita-
tive variables as means ± standard deviation or median (interquartile
range). Binary outcomes from individual studies were combined with
Mantel Haenszel method according to a fixed effect model, leading to
pooled relative risks (RR) with their corresponding 95% confidence in-
tervals (CI) [22]. Cochrane's Q via the χ2
test and I2
were computed to
explore statistical heterogeneity and inconsistency, respectively. A
two-tailed P value b0.05 was considered statistically significant. Analy-
ses were performed using Review Manager (RevMan; version 5.2,
Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration,
2012) and SAS (version 9.2, SAS Institute, North Carolina, USA).
2.4.2. Sensitivity analysis
To verify the consistency of meta-analysis results regarding patients'
outcome, the influence of each individual study on the summary effect
estimate was assessed by the 1-study removed sensitivity analysis
[23]. To explore the influence of potential effect modifiers on outcome,
weighted random-effect meta-regression analysis was performed to
test demographic characteristics of the study population (age and gen-
der), CI-AKI risk factors (including diabetes mellitus and chronic kidney
disease [CKD]), dose of statin, and volume of contrast medium [24,25].
2.4.3. Publication bias
Publication bias was explored by visual inspection of a funnel plot of
precision (standard error of logRR) against the treatment effect (RR on a
logarithmic scale) and using the asymmetry linear regression of Egger's
test [26].
3. Results
3.1. Characteristics of included trials
The flow of study selection for inclusion in the meta-analysis is
shown in Fig. 1. Briefly, we identified 1326 citations from the initial lit-
erature search. After the initial screening, 9 randomized controlled trials
(4, 5, 9, 10, 12, 15–18) with a total of 5212 patients (2593 assigned to
high-dose statin and 2619 assigned to the control arm), satisfying the
inclusion criteria, were identified and analyzed.
The main characteristics of the studies are listed in Table 1. There
were no significant differences in the baseline characteristics be-
tween intensive statin and control groups in terms of age (64 ± 4
and 64 ± 4 years; P = 0.90), diabetes rate (34% and 33%; P = 0.90),
CKD prevalence (45% in both groups), sCr levels (1.01 ± 0.1 and
1.07 ± 0.1 mg/dL; P = 0.90), and total contrast volume (139 ± 32
and 135 ± 39 mL; P = 0.82), respectively.
3.2. Outcome analysis
CI-AKI occurred in 92 (3.5%) subjects allocated to the intensive
statin group and in 186 (7%) subjects allocated to the control group.
The RR for the development of CI-AKI was 0.50 (95% CI 0.39 to 0.64;
P b 0.001) for short-term intensive statin treatment vs. controls
(Fig. 2). No significant heterogeneity among studies was detected
(I2 = 1%; P heterogeneity = 0.42). Subgroup analysis according to
clinical subset (ACS vs. non-ACS patients) was based on 4 randomized
clinical trials in ACS patients (a total of 1134 patients: 563 assigned to
intensive statins and 571 assigned to the control arm) (15–18), and 4
randomized clinical trials in non-ACS patients (a total of 1080 patients:
532 assigned to intensive statins and 548 assigned to the control arm)
(5, 9, 10, 12). In patients with ACS, CI-AKI occurred in 31 (5.5%) subjects
allocated to the intensive statin group and in 85 (15%) subjects allocated
to the control group. The RR for CI-AKI occurrence in intensive statin vs.
control groups was 0.37 (95% CI 0.25 to 0.55; P b 0.0001) (Fig. 3). No
48 G. Marenzi et al. / International Journal of Cardiology 183 (2015) 47–53
3. significant heterogeneity among studies was detected (I2
= 0%; P
heterogeneity = 0.45). In patients without ACS, CI-AKI occurred in 27
(5%) subjects allocated to the intensive statin group, and in 43 (7.8%)
subjects allocated to the control group. CI-AKI rate in patients treated
with intensive statin was lower than in controls, but the difference
did not reach statistical significance (RR 0.65; 95% CI 0.41 to 1.03;
P = 0.07) (Fig. 3). No significant heterogeneity among studies was
detected (I2
= 0%; P heterogeneity = 0.45). Notably, the interaction
test between studies enrolling ACS and non-ACS patients showed a
borderline statistical significance (P = 0.07).
Finally, no significant interaction was found between statin adminis-
tration and time-interval elapsed from randomization to contrast media
exposure (b24 h vs. N24 h before angiography; P = 0.11), cumulative
statin dose before contrast exposure (b80 mg vs. N80 mg; P = 0.61),
and prophylactic treatment with N-acetylcysteine (P = 0.59).
3.3. Sensitivity analysis
Results were confirmed when the meta-analysis was repeated
removing 1 study at a time. By meta-regression analysis, no poten-
tial effect modifiers (including age [slope −0.06; P = 0.32], sex
[slope 0.02; P = 0.15], diabetic status [slope 0.03; P = 0.16], CKD
[slope 0.05; P = 0.17], statin dosage [slope 0.23; P = 0.20], and con-
trast volume [slope 0.01; P = 0.98]) influenced the findings of the
meta-analysis.
3.4. Publication bias
No publication bias was found for the outcome considered in the
analysis and subgroup analysis. Funnel plot was performed for the out-
come and assessed parameters were symmetrically distributed (Fig. 4).
A formal test of publication bias by Egger's test confirmed this observa-
tion (P = 0.51).
4. Discussion
The findings of this meta-analysis, based on the published ran-
domized clinical trials currently available, demonstrated that pre-
procedural, intensive treatment with statins significantly reduces
CI-AKI rate, as compared to a lower dose of statins, no statins, or place-
bo. However, subgroup analysis revealed that the overall benefit was
mainly driven by a significant reduction of CI-AKI incidence in ACS pa-
tients, with only a non-significant positive trend in patients without
ACS.
4.1. CI-AKI
Contrast-induced nephropathy is the third leading cause of acute
kidney injury. Notably, it is associated with increased length of in-
hospital stay, morbidity, mortality, and raised costs of medical care,
especially in patients who require dialysis [1,2]. Moreover, CI-AKI in-
cidence is increasing due to the growing number of contrast proce-
dures being performed and their expanding use in elderly patients
with co-morbidities, such as hypertension, diabetes mellitus, and
CKD, all of which predispose to renal impairment [27]. Preventive
strategies aimed at reducing CI-AKI are of paramount importance
and should directly or indirectly counteract the various factors of
the pathophysiologic cascade leading to CI-AKI [1,2]. On this regard,
increasing evidence suggests that both direct toxicity of contrast
agents on tubular epithelial cells and renal medullary ischemia play
important roles in CI-AKI development, with oxidative stress, vasocon-
striction, injury from chemokines, tubular obstruction, mitochondrial
Fig. 1. Flow of information through the different phases of systematic review from literature search to final analysis. CI-AKI = contrast-induced acute kidney injury.
49G. Marenzi et al. / International Journal of Cardiology 183 (2015) 47–53
4. Table 1
Characteristics of randomized trials included in the analysis.
Trial (Ref #) (year) Inclusion criteria Trial design Statin start
before
CA/PCI (hours)
Patients
(intensive
statin/control, n)
ACS patients
(intensive
statin/control, %)
Mean age
(intensive
statin/control,
years)
Male sex
(intensive
statin/control, %)
DM (intensive
statin/control,
%)
CKDa
(intensive
statin/control,
%)
Han et al. [4] (2014) Type II DM and Stage II/III
CKD
10 mg rosuvastatin vs. no statin 48 1498/1500 79/75 61 ± 9/61 ± 9 64/66 100/100 15/15
Jo et al. [12] (2008) CrCl b 60 or sCr ≥ 1.1 mg/dL 40 mg simvastatin vs. placebo 24 118/118 0/0 65 ± 9/66 ± 8 73/72 28/24 100/100
Leoncini et al. [15]
(2014)
NSTE-ACS 40 mg rosuvastatin vs. placebo 15–44 252/252 100/100 66 ± 12/66 ± 13 66/66 20/23 15/15
Li et al. [17] (2012) STEMI 80 mg atorvastatin vs. placebo 0 78/83 100/100 66 ± 7/65 ± 7 74/77 27/29 N/A
Ozhan et al. [10] (2010) GFR N 70 or sCr b 1.5 mg/dL 80 mg atorvastatin vs. no statin 24 60/70 0/0 54 ± 10/55 ± 8 62/57 15/17 0/0
Patti et al. [16] (2011) NSTE-ACS 80 mg atorvastatin vs. placebo 12 120/121 100/100 65 ± 11/66 ± 10 76/79 30/25 29/32
Quintavalle et al. [5]
(2012)
GFR b 60 and no ACS 80 mg atorvastatin vs. no statin 24 202/208 0/0 70 ± 6/70 ± 8 51/58 44/38 100/100
Toso et al. [9] (2010) CrCl b 60 80 mg atorvastatin vs. placebo 48 152/152 0/0 75 ± 8/76 ± 7 68/60 20/22 100/100
Xinwei et al. [18] (2009) ACS 80 mg simvastatin vs. 20 mg
simvastatin
168 113/115 100/100 65 ± 11/66 ± 12 30/42 20/22 5/4
Baseline sCr (intensive
statin/control, mg/dL)
GFR (intensive
statin/control,
mL/min)
Contrast agent Contrast volume
(intensive statin/control; mL)
CI-AKI additional preventive strategies CI-AKI incidence
(intensive statin/control, n)
Procedure
Han et al. [4] (2014) 1.07 ± 0.24/1.07 ± 0.24 74 ± 14/74 ± 15 Iodixanol 120 (100–200)/110 (100–200)a
Isotonic saline 34/58 CA ± PCI; Periph. proc.
Jo et al. [12] (2008) 1.28 ± 0.41/1.24 ± 0.36 53 ± 16/55 ± 17 Iodixanol 173 ± 99/191 ± 33 Half-isotonic saline 3/4 CA ± PCI
Leoncini et al. [15] (2014) 0.95 ± 0.27/0.96 ± 0.28 70 ± 24/69 ± 25 Iodixanol 150 ± 87/138 ± 78 Isotonic saline and oral NAC 17/38 CA + PCI
Li et al. [17] (2012) 0.93 ± 0.12/0.94 ± 0.12 N/A Iopromide 100 ± 26/104 ± 26 Isotonic saline 2/13 CA ± PCI
Ozhan et al. [10] (2010) 0.88 ± 0.2/0.88 ± 0.2 92 ± 21/89 ± 22 Iopamidol 97 ± 7/93 ± 6 Isotonic saline and oral NAC 2/7 CA ± PCI
Patti et al. [16] (2011) 1.04 ± 0.32/1.04 ± 0.22 80 ± 29/77 ± 28 Iobitridol 209 ± 72/213 ± 73 Isotonic salineb
6/16 CA ± PCI
Quintavalle et al. [5]
(2012)
1.32 (0.96–1.62)/1.29
(0.88–1.61)c
42 ± 13/43 ± 14 Iodixanol 177 ± 74/184 ± 78 Sodium bicarbonate and NAC 7/16 CA ± PCI
Toso et al. [9] (2010) 1.2 ± 0.35/1.18 ± 0.33 46 ± 10/46 ± 11 Iodixanol 151 ± 95/164 ± 99 Isotonic saline and oral NAC 15/16 CA ± PCI
Xinwei et al. [18] (2009) 0.82 ± 0.2/0.83 ± 0.2 94 ± 37/87 ± 30 Iodixanol/Iohexol 227 ± 65/240 ± 78 Isotonic saline 6/18 CA + PCI
ACS = acute coronary syndrome; CA = coronary angiography; CI-AKI = contrast-induced acute kidney injury; CKD = chronic kidney disease; CrCl = creatinine clearance; DM = diabetes mellitus; NAC = N-acetylcysteine; NSTE = non-ST-ele-
vation; GFR = glomerular filtration rate; N/A = not available; Periph. proc. = peripheral procedure; PCI = percutaneous coronary intervention; sCr = serum creatinine; STEMI = ST-elevation acute myocardial infarction.
a
CKD = GFR b 60 mL/min.
b
In CKD patients only.
c
Data expressed as median (interquartile range).
50G.Marenzietal./InternationalJournalofCardiology183(2015)47–53
5. damage, and apoptotic cell death as possible underlying pathogenic
mechanisms [1,2].
4.2. Statins and CI-AKI
Growing evidence suggests that, beyond their lipid-lowering effects,
statins have anti-inflammatory, anti-oxidant, anti-thrombotic, anti-
apoptotic properties, and also ameliorate endothelial function [28].
Short-term statin pre-procedural treatment has been reported to im-
prove outcomes in various clinical settings, and the results have been
attributed to the above-mentioned pleiotropic effects. Specifically,
in ACS patients, pre-procedural statin treatment reduced both peri-
procedural myocardial necrosis during PCI and major adverse cardiac
and cerebral events at short- and long-term follow-up [29–31]. Statins
may also counteract specific pathogenic mechanisms involved in CI-
AKI development.
In 2004, Attallah et al. [20] reported for the first time an observational
study showing a reduction of CI-AKI incidence with statin pre-treatment
in 1002 patients with CKD undergoing CA. In 2005, a review of a large in-
surance database showed that statin pre-treatment was associated with a
lower incidence of CI-AKI after PCI [7]. Since then, several randomized
clinical trials have been performed, some of them supporting these initial
findings, others questioning the usefulness of short-term statin pre-
treatment in the prevention of CI-AKI. Moreover, 3 meta-analyses recent-
ly published on this topic provided conflicting results. Zhang et al. [8] re-
ported a benefit of short-term, high-dose statin treatment in patients
undergoing procedures requiring contrast exposure. A second meta-
analysis reported a non-significant protective trend with statin pre-
treatment [13]. Finally, Zhou et al. [32] found a beneficial effect in the sub-
group of patients with stage N3 CKD only. Thus, no definite conclusion
can be drawn on the efficacy of statins before CA for CI-AKI prophylaxis
in all patients. Among other potential confounders, such as type and
dose of statin, length of pre-treatment, and patients' baseline characteris-
tics, that may explain the heterogeneous results in randomized trials and
meta-analyses performed so far, the clinical setting of patients undergo-
ing invasive procedures may have played an important role.
Fig. 2. Forest plot of risk ratio for contrast-induced acute kidney injury in patients randomized to intensive statin pre-treatment or control treatment. CI = confidence interval; DF = degree
of freedom; M–H = Mantel–Haenszel.
Fig. 3. Upper panel. Forest plot of risk ratio for contrast-induced acute kidney injury in patients with acute coronary syndromes (ACS), randomized to intensive statin pre-treatment or
control treatment. Lower panel. Forest plot of risk ratio for contrast-induced acute kidney injury in non-ACS patients, randomized to intensive statin pre-treatment or control treatment.
ACS = acute coronary syndrome; CI = confidence interval; DF = degree of freedom; M–H = Mantel–Haenszel.
51G. Marenzi et al. / International Journal of Cardiology 183 (2015) 47–53
6. 4.3. Current study
To our knowledge, this is the largest meta-analysis, including more
than 5000 patients, that has been published until now on the use of
statin for CI-AKI prevention. The benefits of short-term, intensive,
pre-procedural statin treatment appeared more prominent in ACS
patients than in patients without ACS although, formally, the
treatment × subgroup interaction test was not fully significant
(P = 0.07), possibly due to the low statistical power of this test and
the limited number of studies and overall events considered in the
analysis.
The mechanisms underlying this difference cannot be inferred from
our data; yet, some hypothesis may be formulated. On one hand, pa-
tients with ACS have a complex systemic homeostatic derangement,
which involves increased inflammatory activity, augmented oxida-
tive stress, abnormal endothelial function and enhanced blood
thrombogenicity [33]. All these mechanisms may play a direct role
in acute renal damage and/or determine a higher susceptibility to
renal injury by iodinate contrast administration. Indeed, CI-AKI rate
was higher in ACS than in non-ACS patients in all the control groups
of the studies included in the subgroup analysis (Table 1). On the
other hand, statins may protect the kidney at different stages of the
pathogenesis of CI-AKI, including: down-regulation of angiotensin
receptors [34], decrease of endothelin synthesis, increase of nitric
oxide bioavailability [35], attenuation of inflammation [36], de-
creased expression of endothelial adhesion molecules [37], limita-
tion of reactive oxygen species production [38], protection against
complement-mediated injury [39], and improved vascular endothelial
growth factor expression [40]. It is worth noting that several of these
putative statin targets may be over-expressed in ACS patients due to
their systemic “activated” metabolic profile, possibly explaining the
more evident protective effect of statins against CI-AKI observed in
these patients. Moreover, the procedures of angioplasty and stenting
may themselves trigger pro-thrombotic activation, distal embolization
of atherothrombotic debris, reperfusion injury, and microvascular dys-
function, thus amplifying the advantages of an early statin intervention
[41–44]. Notably, activation of the thrombotic signaling cascade, in-
flammation, and endothelial dysfunction also characterize patients
with CKD, who are at a higher risk of CI-AKI [1,2]. Therefore, the higher
prevalence of CKD patients enrolled in non-ACS studies than in ACS
studies (88% vs. 17%) may suggest that a lower benefit could have
been observed in non-ACS patients if the distribution of CKD had been
balanced.
The present meta-analysis has several features that distinguish it
from previous meta-analyses [8,13,29]. First of all, we included two ad-
ditional large randomized controlled trials, doubling the population
under study [4,15]. Moreover, these two studies evaluated the effect of
rosuvastatin on CI-AKI incidence for the first time. Lastly, we assessed
the effects of intensive statin pre-treatment on CI-AKI prevention
according to patients' clinical presentation, which was not previously
investigated and may, at least in part, explain the conflicting results of
prior reports.
Taken together, our findings strongly support the use of an intensive
statin pre-treatment in ACS patients. Conversely, its role in non-ACS pa-
tients remains uncertain and further investigation in this population is
warranted.
4.4. Study limitations
The present study has several limitations. First, lack of patient-level
data and inclusion of studies of varying quality and design are limita-
tions common to most meta-analyses. Second, the definition of inten-
sive statin therapy is arbitrary. It is worth noting, however, that no
dose-finding studies with statins for the prevention of CI-AKI have
been reported so far. Third, we considered CI-AKI occurrence within
48 h after contrast exposure only; we therefore acknowledge the possi-
bility that some late events may have been missed [45]. Fourth, two ran-
domized trials published on this topic did not satisfy the inclusion
criteria and were excluded from our analysis. Indeed, the study by
Acikel et al. [6] did not report CI-AKI incidence, whereas the study by
Han et al. [11] was published as a brief communication. Finally, the
existing data do not fully address whether intensive, pre-procedural
statin therapy has an impact on clinical outcomes, besides the effect
on CI-AKI incidence.
4.5. Conclusions
The results of the present meta-analysis support the use of intensive,
pre-procedural statin therapy to reduce the risk of CI-AKI in ACS pa-
tients, which may contribute to the overall clinical benefit associated
with the early use of these drugs in this clinical setting. Prospective
studies are warranted to better identify the preferable statin, to as-
sess the optimal dose for achieving kidney protection, and to establish
whether this pharmacological approach translates into short- and
long-term clinical benefits. The role of statins for CI-AKI prevention in
non-ACS patients remains uncertain.
Sources of funding
Funding for this study was provided by the Centro Cardiologico
Monzino, I.R.C.C.S., Milan, Italy.
Conflict of interest
None reported.
Acknowledgment
None.
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